Cure rates for patients with multiply relapsed or metastatic solid tumors, particularly sarcomas, remain <30% despite aggressive multimodal therapy including surgery, radiation, and chemotherapy. Our preliminary data suggest highly malignant sarcomas in animal models are susceptible to killing by attenuated herpes simplex virus mutants, such as the ICP6 mutant rRp450. These "oncolytic" mutant viruses are lytic for many types of cancer cells, but are attenuated in their ability to replicate in normal cells. The mechanisms of cytotoxicity induced by these agents circumvent traditional cancer-resistance mechanisms. Adequate preclinical testing of the efficacy of these agents in an immunocompetent setting has been difficult, particularly for metastatic disease, because of the lack of appropriate tumor models. Here we will exploit a remarkable new mouse model, transgenic for hepatocyte growth factor/scatter factor (HGF/SF-tg) and null for the tumor suppressor locus p16 -INK4A/ARF, to investigate lytic HSV cancer therapy. Nearly 100% of these mice develop spontaneous, highly invasive rhabdomyosarcomas in the first few months of life. Unlike many previous studies of rodent tumor models, our data show cell lines derived from these tumors support robust replication of attenuated HSV mutants. Furthermore, intravenous HSV preferentially targets tumor relative to normal tissues, and improves survival of mice with pulmonary metastases. Intratumoral virus injection results in a marked tumor infiltration of activated T lymphocytes including regulatory T cells. Our overarching hypothesis is that control of local and metastatic sarcoma can be achieved in immunocompetent cancer models using a highly lytic but attenuated HSV mutant, and that the antitumor activity is driven by both viral and immune-mediated cytolytic effects. Furthermore, elucidation of the mechanisms of virus targeting to metastatic sites and regulation of the immune response will permit rational design of strategies to improve cancer control with these agents. Our long-term goal is to better understand the therapeutic effects of oncolytic HSV mutants for cancer. We will test our hypotheses using an HSV-susceptible, immunocompetent mouse sarcoma model that emulates human disease more closely than previously possible. Our aims are: Aim 1: Determine the mechanism of systemic HSV tumor targeting in the setting of multiple sites of metastases. Aim 2: Test the effect of antiangiogenic agents on the systemic delivery and antitumor efficacy of oncolytic HSV. Aim 3: Define the role of cytotoxic and regulatory T cells in tumor shrinkage following intratumoral HSV therapy. These studies will elucidate mechanisms of tumor-selective virus delivery and immunologic-mediated cytotoxicity and test specific strategies to improve the antitumor effect of oncolytic HSV for metastatic disease. Our results will guide the design of future clinical trials using these novel agents.